I have been a post-doctoral research fellow in the lab of Dr. Dennis Choi since finishing my residency in neurology at Stanford 2 years ago. I am fully committed to an academic research career, and to prepare myself as best as possible, have enrolled in the neurosciences PhD program (class requirements will be finished in Fall 1989.) Work in Dr. Choi' s lab primarily involves toxicity and neurophysiological studies on cortical neuronal cultures. However, there is a broad range of expertise in the neurology and neurobiology departments, and informal collaborations and help with techniques are easy to arrange. The proposed study seeks to investigate the neurotoxicity of the atypical excitatory amino acid (EAA), beta-N-methylamino-L-alanine (BMAA), beta-N-oxalylamino-L-alanine (BOAA) and other non-NMDA agonists on cortical neuronal cultures. The motivation for the project derives from interest in the potential role of chronic EAA toxicity in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS), a hypothesis strengthened by evidence that ingestion of BMAA may contribute to the pathophysiology of the ALS - Parkinsonism - dementia complex of Guam, a human disease with features of ALS and AD. We have found that low concentrations of BMAA (like BOAA, which causes lathyrism) may be able to produce selective neuronal injury through the activation of non-NMDA receptors and are therefore intrigued by the possibility that non-NMDA receptor activation contributes to the pathophysiology of neurodegenerative diseases. We will explore the chronic toxicity of BMAA and non-NMDA agonists on subsets of neurons, to determine whether classes of neurons lost in AD or ALS are selectively vulnerable to these toxins. We will then explore the role of calcium and other cellular mechanisms in the neuronal injury, and, in late stages, the toxicity of these compounds will be explored in animals.